Liposomal doxorubicin (Caelyx) in advanced pretreated soft tissue sarcomas: a phase II study of the Italian Sarcoma Group (ISG).

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BACKGROUND: Doxorubicin remains one of the few drugs with consistent single agent activity in advanced Soft Tissue Sarcomas (STS), with a demonstrated dose-response relationship. Liposomal-encapsulated Doxorubicin (LED) has been shown to be at least as active as free doxorubicin in experimental models, and phase I and II human studies indicate that this novel strategy of drug delivery my have less myocardial toxicity. Few clinical trials in adult STS have been published until now, with disappointing and often contrasting results. PATIENTS AND METHODS: Twenty-five consecutive patients with measurable advanced and/or metastatic STS, previously pretreated with anthracycline-based chemotherapy, were enrolled into the trial. LED (Caelyx) was administered over 1-hour intravenous infusion at the dose of 30 mg/m2 in the first 5 patients, then at the fixed dose of 50 mg/m2 in the subsequent 20 patients. Treatment was given on ambulatory basis, at 3-week intervals. Antiemetics were generally not required and only used if indicated. RESULTS: A total of 98 courses of chemotherapy were given (median 4 per patient, range 2 to 5). Amongst the 25 evaluable patients, there were 3 partial responses (12%, 95% confidence interval 4.2% to 29.9%) lasting 3-9+ months and all occurring in patients treated at 50 mg/m2/cycle. In addition, 2 minor responses (4+ months) and 17 stable disease (2-7+ months) were observed; the remaining 3 patients progressed while on therapy. The median delivered drug dose-intensity was 13.3 mg/m2/week (range 10 to 16.6 mg/m2/week). Treatment was well tolerated, with no patient requiring dose reduction or therapy delay because of toxicity. Only 2 cases of WHO grade 3 toxicity occurred, consisting of neutropenia and scrotal skin toxicity; respectively; no cardiotoxicity was seen. CONCLUSIONS: This study shows that Caelyx has some activity in advanced, anthracycline-pretreated STS, with favourable toxic profile. From the analysis of available experiences it emerges that liposomal doxorubicin has not been tested at doses adequate to exploit the antitumor effects of the drug, being the reached dose-intensity being even lower than those deemed critical for obtaining optimal responses to free doxorubicin. We suggest that further and better addressed studies be performed in STS, including patients with less advanced stages of disease, focused on attempting to delivery the drug at optimal doses.

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